Bipolar disorder is a progressive psychiatric disorder (F. Goodwin and K. R. Jamison, Manic-Depressive Illness, Oxford University Press, New York, 1990). Bipolar disorder is characterized by recurrent episodes of changes in mood. The episodes may exhibit symptoms of mania, hypomania (less severe form of mania), depression, or a combination of mania and depression (Bipolar Disorder, Cognos Study #53, Decision Resources, March 2000). Bipolar disorder type I features more manic or mixed mood symptoms, while bipolar disorder type II is distinguished by primarily depressive episodes but also by spontaneous hypomanic episodes (Diagnostic and Statistical Manual of Mental Disorders, Edition 4, American Psychiatric Association, Washington D.C., 1994; Bipolar Disorder, Cognos Study #53, Decision Resources, March 2000; Akiskal H. S., Bourgeois M. L., Angst J., Post R., Moller H., Hirschfeld R., Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders, J. Affect. Disord., 2000, 59 (Suppl 1), S5–S30). Acute mania is associated with an elevated or irritable mood and at least three to four classical mania signs and symptoms (e.g., abnormally elevated or irritable mood, grandiosity or inflated self-esteem, decreased sleep, racing thoughts, distractibility) (Diagnostic and Statistical Manual of Mental Disorders, Edition 4, American Psychiatric Association, Washington D.C., 1994). Hypomania is associated with a period of mild mood elevation, sharpened positive thinking and increased energy and activity levels, but without the impairment associated with maniac episodes (Diagnostic and Statistical Manual of Mental Disorders, Edition 4, American Psychiatric Association, Washington D.C., 1994). Rapid cycling is defined as alternation of depression and mania/excitation (Akiskal H. S., Bourgeois M. L., Angst J., Post R., Moller H., Hirschfeld R., Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders, J. Affect. Disord., 2000, 59 (Suppl 1), S5–S30). Cyclothymic disorder is an attenuated bipolar disorder characterized by frequent short cycles of subsyndromal depression and hypomanic episodes (Diagnostic and Statistical Manual of Mental Disorders, Edition 4, American Psychiatric Association, Washington D.C., 1994).
Recurrences of bipolar disorder illness have been hypothesized to be caused by electrophysiologic/neurophysiologic kindling (F. Goodwin and K. R. Jamison, Manic-Depressive Illness, Oxford University Press, New York, pp 405–407,1990; Ghaemi S. N., Boiman E. E., Goodwin F. K., Kindling and second messengers: an approach to the neurobiology of recurrence in bipolar disorder, Biol. Psychiatry, 1999, 45(2), 137–44; Stoll A. L., Severus W. E., Mood stabilizers: shared mechanisms of action at postsynaptic signal-transduction and kindling processes, Harv. Rev. Psychiatry, 1996, 4(2), 77–89; Goldberg J. F., Harrow M., Kindling in bipolar disorders: a longitudinal follow-up study, Biol. Psychiatry, 1994, 1; 35(1), 70–2).
Mood stabilizers are used to treat bipolar disorder (Sadock B. J., Sadock B. A., Post RM. Treatment of bipolar disorders, Comprehensive Textbook of Psychiatry, 2000, vol. 1, 1385–1430). Established mood stabilizers exhibit anti-kindling effects (Stoll A. L., Severus W. E., Mood stabilizers: shared mechanisms of action at postsynaptic signal-transduction and kindling processes, Harv. Rev. Psychiatry, 1996, 4(2), 77–89). Anticonvulsants and anti-epileptics which show anti-kindling effects are important alternatives and adjuncts in the treatment of bipolar illness (Post R. M., Denicoff K. D., Frye M. A., Dunn R. T., Leverich G. S., Osuch E., Speer A., A history of the use of anticonvulsants as mood stabilizers in the last two decades of the 20th century, Neuropsychobiology, 1998, 38(3), 152–66; Janowsky D. S., New Treatments of Bipolar Disorder, Curr. Psychiatry Rep., 1999, 1(2), 111–113) including in rapid cycling bipolar disorder (Shelton M. D., Calabrese J. R., Current Concepts in Rapid Cycling Bipolar Disorder, Curr. Psychiatry Rep., 2000, 2(4), 310–315) and in the treatment and prevention of acute mania (Lennkh C., Simhandl C., Current aspects of valproate in bipolar disorder, Int. Clin. Psychopharmacol, 2000, 15(1), 1–11; Tohen M., Grundy S., Management of acute mania, J. Clin. Psychiatry, 1999, 60 (Suppl 5) 31–4; Muller-Oerlinghausen B., Retzow A., Henn F. A., Giedke H., Walden J., Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania: a prospective, randomized, double-blind, placebo-controlled, multicenter study, European Valproate Mania Study Group, J. Clin. Psychopharmacol., 2000, 20(2), 195–203; Sachs G. S., Printz D. J., Kahn D. A., Carpenter D., Docherty J. P., The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000. Postgrad. Med., 2000, Spec No: 1–104).
Substituted phenyl alkyl carbamate compounds have been described in U.S. Pat. No. 3,265,728 to Bossinger, et al (hereby incorporated by reference), as useful in treating the central nervous system, having tranquilization, sedation and muscle relaxation properties of the formula:
wherein R1 is either carbamate or alkyl carbamate containing from 1 to 3 carbon atoms in the alkyl group; R2 is either hydrogen, hydroxy, alkyl or hydroxy alkyl containing from 1 to 2 carbons; R3 is either hydrogen or alkyl containing from 1 to 2 carbons; and X can be halogen, methyl, methoxy, phenyl, nitro or amino.
A method for inducing calming and muscle relaxation with carbamates has been described in U.S. Pat. No. 3,313,692 to Bossinger, et al (hereby incorporated by reference) by administering a compound of the formula:
in which W represents an aliphatic radical containing less than 4 carbon atoms, wherein R1 represents an aromatic radical, R2 represents hydrogen or an alkyl radical containing less than 4 carbon atoms, and X represents hydrogen or hydroxy or alkoxy and alkyl radicals containing less than 4 carbon atoms or the radical:
in which B represents an organic amine radical of the group consisting of heterocyclic, ureido and hydrazino radicals and the radical —N(R3)2 wherein R3 represents hydrogen or an alkyl radical containing less than 4 carbon atoms.
Optically pure forms of halogen substituted 2-phenyl-1,2-ethanediol monocarbamates and dicarbamates have also been described in U.S. Pat. No. 6,103,759 to Choi, et al (hereby incorporated by reference), as effective for treating and preventing central nervous system disorders including convulsions, epilepsy, stroke and muscle spasm; and as useful in the treatment of central nervous system diseases, particularly as anticonvulsants, antiepileptics, neuroprotective agents and centrally acting muscle relaxants, of the formulae:
wherein one enantiomer predominates and wherein the phenyl ring is substituted at X with one to five halogen atoms selected from fluorine, chlorine, bromine or iodine atoms and R1, R2, R3, R4, R5 and R6 are each selected from hydrogen and straight or branched alkyl groups with one to four carbons optionally substituted with a phenyl group with substituents selected from the group consisting of hydrogen, halogen, alkyl, alkyloxy, amino, nitro and cyano. Pure enantiomeric forms and enantiomeric mixtures were described wherein one of the enantiomers predominates in the mixture for the compounds represented by the formulae above; preferably one of the enantiomers predominates to the extent of about 90% or greater; and, most preferably, about 98% or greater.
A halogen substituted 2-phenyl-1,2-ethanediol dicarbamate enantiomer of Formula (I) or enantiomeric mixture wherein one enantiomer of Formula (I) predominates has not been previously described as useful for preventing or treating bipolar disorder. Recent preclinical studies have revealed previously unrecognized pharmacological properties which suggest that an enantiomer of Formula (I) or enantiomeric mixture wherein one enantiomer of Formula (I) predominates is useful in preventing or treating bipolar disorder. Therefore, it is an object of the present invention to teach a method for use of an enantiomer of Formula (I) or enantiomeric mixture wherein one enantiomer of Formula (I) predominates in preventing or treating bipolar disorder.